Antacid preparations containing acrylic acid polymers and magnesium antacids



Unimd States Paten ANTAC 'D PREPARATIONS CONTAINING ACRYL- IC AgmPOLYMERS AND MAGNESIUM ANT- ACID Ludwig A. Staib, Jr., Elizabeth, N.J.,assignor to Bristol- Myers Company, New York, N.Y., a corporation ofDelaware No Drawing. .Application November 2, 1955 Serial No. 544,597

17 Claims. (Cl. 167-55) The present application is a continuation-impartof my copending application, Serial No. 488,422, filed February 15,1955, now abandoned.

This invention relates to pharmaceuticals and more particularly to a newtype of antacid preparation which may be taken in any required amount,without harmful elfect, by those who suffer from excess acidity,including persons having ulcers of the stomach or intestines.

A largenumber of substances are known which will raise the pH of thestomach and thus relieve temporarily the distress which results fromhyperacidity. For example, bicarbonate soda is a well known substance ofthis character. However, this and many other substances have a tendencyto raise the pH of the stomach to an excessively high value, soon afterthey are taken, with the result that the human system promptly reacts togenerate more acid to overcome the alkalinity of the stomach. Such acidrebound quickly restores the condition which caused the originaldistress. Thus if the stomach originally had a pH of 2 or lower, theantacid frequently boosts the pH to a higher range for a brief periodbut the acid rebound rather quickly bring the pH back to its originallow value or even somewhat lower.

. Various antacid preparations have been developed which overcome theobjectionable acid rebound reaction but these act more slowly inrelieving the distress. An example of such a preparation is aluminumhydroxide. This has been found to raise the pH of the stomach to onlyabout 4.5 but it acts relatively slowly and does not bring the pH up to4 until about 20 to 30 minutes after a usual dose has been taken. Exceptfor the slowness in relieving distress, this preparation provides adesirable antacid effect.

Various buffered antacid preparations have been developed combining thequick action of such substances as bicarbonate of soda and the longeraction of such substances as aluminum hydroxide.

However, many previously known forms of antacid preparations have aconstipating effect which is particularly serious in the case of personshaving ulcers, since they are required to take an antacid preparation atrather frequent intervals. To olfset the constipating action of antacidsit has frequently been the practice to take with an antacid preparationsome form of active laxative but 2,912,358 Patented Nov. 10, 1959 tion.An objection to these is that they prevent the ab-.

sorption of oil-soluble materials, such as the oil-soluble vitamins (A,D, E and K) through the intestinal wall. A fourth type of laxative maybe classified as bulk laxatives. These include agar-agar, bran,carboxymethylcellulose, methyl cellulose andcertain of the vegetablegums. These materials provide bulk by swelling as soon as they come incontact with water. While this action is desirable when confined to theintestinal tract, it produces discomfort and even more seriousdifliculties when it occurs in the stomach. To avoid this it is usuallynecessary to add certain ingredients such as glycerine or sorbitol,which are gastrointestinal irritants.

A primary object of the present invention has been to provide a newantacid preparation which will give prompt 1 relief from distress due tohyperacidity, will not raise the pH of the stomach above about 5.5, andpreferably not above 4.5, so as not to induce acid rebound, and whichwill be non-constipating while imparting no more than a mild bulklaxative action and without requiring the presence of gastrointestinalirritants.

Another object has been to provide a process for the treatment ofhyperacidity which does not give rise' to constipation or to acidrebound or to discomfort or irritation of the stomach or intestines, anddoes not interfere with the absorption of desirable nutritive materialsinto the human system.

It has been discovered that certain mixtures of an antacid, such as theoxide, hydroxide, carbonate, or a mixture will provide, up'on oraladministration, the quick acting effect of the magnesium oxide orhydroxide but will be bulfered by the action of the crosslinked acrylicacid polymer so that the pH of the stomach will not be raisedappreciably above 5.5, and preferably not above 4.5, and the pH will bemaintained below this point for a relatively long period of timewhen asuitable dose of the preparation is taken. Moreover, as the antacidpreparation passes out of the stomach and into the intestines, thecrosslinked polymer of acrylic acid will swell and become gelled at thepH present there.

To produce an adequate antacid eifect it is desirable to provide anexcess of substances capable of raising the pH of the stomach, but thecharacter and quantity of these substances employed should not be suchas to raise the pH of the stomach for any appreciable length of timeabove about 5.5, and preferably not above about 4.5, otherwise anobjectionable acid rebound will occur which will oifset the usefulnessof the antacid. It has been found that a crosslinked, colloidallywater-soluble'polymer of acrylic acid such as defined hereinbelow iscapable of buffering the alkalizing effect of a suitable excess of suchsubstances as magnesium oxide or hydroxide, which in the absence:acrylic acid would provide" of the crosslinked polymer of anobjectionably high pH;

Thus it has beenfoundthat if half a gram of magnesium hydroxide or oxideis intermixed with half a gram o f'a' colloidally water-soluble linkedwith between about 0.75% and 1.5 and preferpolyrner of acrylic acidcross-' ably about 1.0%, by weight of allyl sucrose, a very desirableantacid effect will be produced. The pH of the stomach will be ratherquickly raised from a point below 2 to a point normally between about 4and 5 and will be maintained at a suitable level for a substantialperiod of time.

The resins which are contemplated as useful in the present antacidcompositions include non-toxic, nonirritating colloidally water-solublepolymers of acrylic acid crosslinked with a polyhydroxy compound havingat least 3 and preferably not more than about 8 hydroxyl groups, whereinthe hydrogen atoms of at least three hydroxyl groups are replaced withunsaturated aliphatic radicals having two or more carbon atoms.Preferred radicals are those containing from two to four carbon atoms,e.g., vinyl, allyl or crotyl. These unsaturated radicals may themselvescontain other substituents, such as the methyl group. For example, themethallyl radical is useful.

The polyhydroxy compounds useful in the formation of the cross-linkingmaterials contemplated by the present invention preferably contain threeor more hydroxyl groups and may include saccharides, for example,monosaccharides such as glucose, fructose, mannose or galactose anddisaccharides such as sucrose, maltose, or lactose. Other usefulpolyhydroxy compounds include polyhydroxy alcohols, such as glycerol,erythritol, dulcitol, mannitol, sorbitol and pentaerythritol. Theunsaturated crosslinkers described above are all ethers but I alsocontemplate the use, as crosslinking materials, of unsaturated esters,such as the triacrylic acid ester of glycerol or acrylic acid esters orsucrose having from 3' to 8 acid residues. Unsaturated ether-esters mayalso be used, but as in the case of unsaturated esters, are notpreferred because of their tendency to hydrolyze in aqueous solutions.

The preferred crosslinking compounds are polyallyl sucrose, preferablycontaining from 5 to 8 allyl groups per sucrose molecule and polyallylpentaerythritol preferably tetraallyl pentaerythritol.

In each case, the crosslinker preferably comprises from about 0.75% toabout 1.5% by weight of the crosslinked material.

The synthetic resins comprising any of the aforementioned components areprepared by reacting acrylic acid or a similar monomeric resin-formingmaterial with a cross-linking material, in the presence of a catalyst,under autogenous pressure and in an inert atmosphere to inhibitoxidation. A suitable catalyst, for example, a peroxide, such as benzoylperoxide or caproyl peroxide, is used in a concentration of from 0.1% to2%. The reaction is carried out in the presence of an inert diluentwhich will not copolymerize with the reactants and which will not resultin swelling of the polymerized product. Such diluents preferably shouldbe solvents for the monomers but not for the polymers resulting from thereaction and may include water, alcohol, or saturated aliphatic oraromatic liquid hydrocarbons. Preferred diluents include such liquidhydrocarbons as benzene or toluene. However, solvents for the monomersare not essential, for the reaction may be conducted as an emulsionpolymerization although this type of reaction is not preferred. Thereaction is an exothermic one and may be carried out with simpleagitation in a reactor provided with simple wall-cooling; thetemperature being held between 20 C. and 70 C., preferably about 50 C.The reaction temperature is not critical but if held much below 50 C.,the rate of reaction may be quite slow, Whereas if the temperature isallowed to go much above 50 C., the exothermic reaction may proceed tooviolently. The polymerization is carried as far toward completion aspossible, the time required varying greatly with the reacting materialsand other factors. If the reaction is carried out in the presence of aninert diluent as specified above, the progress of the reaction may befollowed by periodically sampling the liquid phase and analyzing it forthe presence of the free monomer. In such case, the reaction isdetermined to be complete when the percentage of monomer reaches aminimum concentration. In practice substantially of the monomericmaterial is converted during the reaction to the polymeric form.

An example of a specific product prepared in accordance with the aboveprocedure is a product made by the B. F. Goodrich Chemical Company andwhich is designated by the trademark Carbopol-934, formerly known asGood-rite 14-934. This product is a colloidally water-soluble polymer ofacrylic acid crosslinked with approximately 1% by weight of allylsucrose, the latter material having an average of about 5.8 allyl groupsper molecule. This product is prepared by mixing the acrylic acidmonomer and the allyl sucrose in the presence of a toluene diluent and1% of benzoyl peroxide and the reaction allowed to proceed to completionat which time the diluent, together with unreacted monomer and catalyst,is removed by filtration and subsequent volatilization from the solidpolymeric residue. The polymer thereby obtained is in the form of awhite powder having a maximum particle size of 10 mesh and a bulkdensity of about 12 pounds per cubic foot. The exact molecular weightis, of course, unknown but analysis shows that the product has anequivalent weight (molecular weight per repeating unit) of about 77. Theminimum molecular weight, as roughly determined from viscositymeasurements, is probably about 200,000.

The viscosity of a resin, made in accordance with the foregoingprocedure, was determined by the following procedure. A 2.5 gram sampleof resin was sifted into 500 ml. of distilled water in a Waring Blendorrun at low speed and mixed for three minutes. The resulting 0.5%colloidal solution was transferred to a one liter beaker and allowed tostand until the foam broke. The pH was then adjusted with ammoniumhydroxide to 6.5-7.0, and the solution stirred for 30 seconds at 250rpm. The resulting gel was allowed to stand for one hour at 25 C. and aviscosity test was then run with a Brookfield viscosimeter using anumber 4 spindle at 60 rpm.

The above test was repeated elevent times, using for each of the tests asample from a different lot of resin. The average viscosity was found tobe 71:7 poises.

When tested in a manner similar to the procedure described above, oneform of crosslinked acrylic acid polymer found desirable for use inaccordance with the invention gave a pH of 3 and a viscosity of 24.0centipoises when dispersed to the extent of a 1% aqueous sol. When thepH of this colloidal solution or sol was adjusted to about 3.6 withdilute alkali, the viscosity increased to 264.0 centipoises. Uponfurther increase of the pH to about 4.3 the viscosity increased to about6,500 centipoises. On increasing the pH to about 6.0, where maximumgelation seems to occur, the resulting gel becomes firm and is soviscous that its viscosity is almost impossible to measure. Uponincreasing of pH to above about 9 or 10, the gel again decreases inviscosity. The colloidal gel, derived from the relatively small amountof polyacrylic acid contemplated in accordance with the invention, hasthe desirable bulk properties which provide the non-constipating effectdesired. When the pH of the colloidal gel or sol is lowered, theviscosity is observed to decrease. However, when the pH is reduced below3, the viscosity is not materially lowered below 24 centipoises, whichwas observed at this pH.

One form of the crosslinked acrylic acid polymer containing 1% of allylsucrose crosslinker desirable for employment in preparing thecompositions of the invention is a white dry powder, which does not havea melting point. Instead of melting, it changes color at about C. andbecomes quite dark at about 260 C.

Within a relatively wide temperature range the material is stable sothat it will withstand autoclaving, and it is not degraded by moderateamounts of acid or alkali. The material is substantially non-toxic,odorless, colorless, and it might be said to have a slightly sour taste.It is bland, causes no irritation and appears to be non-habit forming.When this crosslinked polymer is dispersed in water to the extent of a1% sol it is found to provide a pH to the solution of approximately 3.

The crosslinked acrylic acid polymers desirable for use in thecompositions of the invention are considered to be colloidallywater-soluble, or sol-forming, and are herein described as such.Although their aqueous sols may contain no suspended matter whichsettles upon standing, they are not true solutions in the crystalloidsense and may be more accurately described as colloidal suspensions I orsolutions (sols). While none of the material will settle out uponstanding, if subjected to ultra-centrifuging, much of this material,being colloidal in nature, may be separated from its colloidal solutionor suspension. These aqueous sols give the characteristic Tyndall effectof aqueous colloidal dispersions.

Suitable compositions in accordance with the invention may be obtainedby intimately intermixing various quantitles by weight of a colloidallywater-soluble, crosslinked polymer of acrylic acid of the characterindicated above, and a suitable antacid, such as an oxide, hydroxide,carbonate, or basic salt of magnesium, including the basic carbonate ofmagnesium known as magnesium abla. In a mixture of the crosslinkedpolymer of acrylic acid with one of the antacid ingredients, the lattershould be in excess of stoichiometric proportions required to react withthe crosslinked polymer of acrylic acid. Thus it has been found that theequivalent weight of polyacrylic acid cross- I linked with about 1% ofallylsucrose, i.e., the average molecular weight per repeating unit'inthe polymer structure, is 77 and that one equivalent weight of such apolymer chemically combines with /2 mole, i.e., approximately 29 gramsof magnesium hydroxide to yield a magnesium salt of the polyacrylicacid. If a greater antacid efiect is desired, a larger proportion of theantacid ingredient may be employed. For example, for each gram of thecrosslinked polymer of acrylic acid there may be used either 1 gram, 1.5grams, 2 grams or 3 grams, or more up to 6 grams of one of the antacidcomponents mentioned, such as magnesium hydroxide. It has been found,however, that if the antacid ingredient is present in too great anexcess, as for example in a 16 to 1 ratio by weight, the compositionwill behave in a manner similar to the straight antacid component. ThepH will then increase too rapidly and the buffering action will takeplace at too high a pH. Therefore, it is not generally desirable toinclude a higher content of the antacid component than about a 6 to 1ratio.

While the pH of the stomach will be raised to a point above about 4 upontaking the compositions of the present invention, due to the antacidingredient embodied in it, this will produce some, but notobjectionable, bulking of the crosslinked polymer of acrylic acid in thestomach. When the proper dosage of the composition is taken the quantityof the colloidally water-soluble polymer of acrylic acid present willnot be sufficient to create an uncomfortable feeling of fullness.Moreover, the polymer of acrylic acid provides a buffering action whichprevents the pH of the stomach from rising substantially above 5.5, andpreferably not above 4.5, and while at the latter pH the viscosity ofthe crosslinked polymer of acrylic acid will be greatly increased, suchincrease is by no means comparable to the increase in viscosity whichresults at a pH of 6 or higher. In fact, a beneficial action appears totake place as a result of the increase in viscosity of the crosslinkedpolymer of acrylic acid component of the composition when the stomachattains a pH of about 4.5. This increase in viscosity tends to retardthe discharge of the composition from the, stomach through the pylorusinto the duodenum. In this way it is more likely that the antacidcomponent of the composition will remain in the stomach long enough toprovide its full effect before it passes through the pylorus. As the pHof the stomach drops to a point around 3, which occurs after the antacidcomponent has been spent, through the continual process of generation ofhydrochloric acid within the system, the crosslinked polymer of acrylicacid will have its viscosity lowered to a point commensurate with thatoriginally attained at a pH of 3. Accordingly, it becomes sufficientlyfluid by that time, and even at a somewhat eai 'lier stage, to passfreely through the pylorus. Upon reaching the intestinal region,however, where a pH of 6 or higher is present, the colloidallywater-soluble, cross-linked polymer of acrylic acid will assume theform' of a firm gel having an exceedingly high viscosity, which providesthe desired bulking and eliminating action. The eliminating action isachieved without irritation of the intestines. Moreover, while the gelor jelly has certain lubricating qualities it does not have theobjectionable action of mineral oil, and the like, of preventing theabsorption through the intestinal wall of beneficial oil-solublematerials, such as oil-soluble vitamins. I

To illustrate the character of the gel formed at a relatively high pH,it may be mentioned that a 1% gel of the colloidally water-soluble,crosslinked polymer of acrylic acid at a pH of 7 was found to retain itsform and water content in the face of centrifugation creating a forceequal to 20,000 times that of gravity. It will be readily apparent thata comparatively small amount of the polymer of acrylic acid in this formis sufiicient to bring about the bulking action in the intestinesnecessary to offset the constipating elfect of the antacid ingredientitself.

While the new composition of the invention may, if desired, be taken inliquid form, i.e., as a solution or. suspension of the ingredients in anon-aqueous medium such as ethyl alcohol, glycerine, coconut or otheredible vegetable oil, this is not ordinarily desirable because of therather high viscosity of the substance which may'result from theelevated pH which may be imparted to the com positions by the antacidcomponent. In the case of magnesium oxide, hydroxide, carbonate orhydroxy salt of magnesium, the gelling of the crosslinked polymer ofacrylic acid is not as rapid as with certain other antacids, and, ifadministered reasonably promptly, liquid compositions employing thesemagnesium antacids Will not have time to form a gel. For the same reasonit is not ordinarily preferred to provide the new composition in theform of a granulation, to be stirred into a glass of 1 water prior totaking, although if the resulting aqueous.

composition employs one of the magnesium antacid components describedabove it will not become appreciably viscous if taken promptly by theuser, and may be dispensed in this form. Preferably the composition istaken in the form of a dry tablet. Such a tablet may be produced from.the mixture of a colloidally watersoluble, crosslinked polymer ofacrylic acid and an antacid component, such as the oxide, hydroxide,carbonate or bydroxy salt of magnesium, with the addition of suitablebinders or tablet-forming constituents, such as gelatin, gum acacia, gumtragacanth, pectin or other vegetable and biological gums. In addition,there may be added inert diluents such as starch, talc, terra alba, andthe like, to provide body. By inert diluents I mean substances of thecharacter indicated which are non-toxic and will not react unfavorablywith or upon either the human system or the active ingredients of thepreparation. It should not have a hydrolytic, decomposing or untowardeffect upon the active constituents. The binderemployed may' also beconsidered a diluent and should be inert in the sense indicated.

As a typical example of a tablet formed in accordance with theinvention, there may be thoroughly intermixed 36 parts of colloidallywater-soluble polymer of acrylic acid crosslinked with 1% of allylsucrose, 36 parts of magnesium oxide, and 3 parts of pectin, alldetermined by weight. After thorough intermixture of these ingredientsthey may be triturated with a mixture of chloroform and acetone. Afterthorough mixing the composition is dried and the chloroform and acetoneare driven off by heat in a drying oven. Subsequently 25 parts, byweight, of the diluent, such as starch, may be mixed with the otheringredients. The resulting mixture may then be pressed into tablets ofsuitable size.

A suitable dosage of the above tablet composition is that which willcontain .5 gram of the crosslinlted poly mer of acrylic acid and .5 gramof magnesium oxide. Therefore, a tablet having the composition suggestedabove should weigh 1.39 grams. If desired, each tablet may be made tocontain 0.7 gram of the composition and 2 such tablets may be taken asan appropriate dose. it will be understood that the amount of thecomposition to be taken as a dose may be varied in accordance with thecircumstances. In severe cases of hyperacidity a larger amount of thepreparation may be taken as a single dose, or the tablets may be takenat more frequent intervals than in milder cases. In general it may besaid that from 1 to 4 of the 0.7 gram tablets may be taken as a singledose.

Tablets containing magnesium hydroxide and the colloidallywater-soluble, crosslinked polymer of acrylic acid in the ratio of about3 parts to 1 by weight are preferred. Thus, the preferred tabletcomposition in ac cordance with the present invention contains thefollowing composition for each tablet.

Gram Magnesium hydroxide 0.300 Gelatin 0.015 Polymer of acrylic acidcrosslinked with 1% by weight of allyl sucrose (Carbopol934) 0.100

Total weight of tablet 0.415

trostatic charge, the latter fact making accurate determination of sizedistribution of the polymer particles quite difficult to obtain byreason of the tendency of the charged particles to fly apart and toadhere to handling apparatus. This tendency also makes it extremelydilficult to use the untreated polymer powder in the formulation ofpharmaceutical preparations.

Therefore, the present invention contemplates the use in pharmaceuticalantacid preparations of a crosslinked polymer of acrylic acid which hasbeen subjected to steam to agglomerate the resin and to vitiate theeffects of the electrostatic charge carried by the polymer in itsinitial finely divided form.

For example, a polyacrylic acid resin, crosslinked with allyl sucroseand produced as described herein, placed in a shallow tray in anenclosed housing and treated with steam at a dry bulb temperature of 210F. and a wet bulb temperature of 190 F. for 45 minutes, after which timethe wet bulb temperature was reduced to 100 F. and heating was continuedat a dry bulb temperature of 200 F. for another 80 minutes.

The resin subjected to the steaming process is chemically unchanged butis physically agglomerated into a porous cake which is then milled. Theproduct of the milling procedure is screened and the material having aparticle diameter less than 40 mesh (0.015 inch) is retained forsubsequent formulation. This material has a particle size distributionas shown in the following table:

Sieve Aperture Width Percent m Retained 0n Sieve Mesh N0. Inches Microns1 33 21 8 124- 15 less than 124..- 22

In contrast to the relatively large particle size of the steamed andmilled polymer, the particle size of the allyl sucrose crosslinkedpolymer of acrylic acid, when produced by a process such as thatdescribed hereinabove, is from about 10 to about 50 microns.

Despite the increased particle size of the treated polymer, the bulkdensity of the latter is much greater than that of the untreatedpolymer. This is of great advantage in formulating pharmaceuticalproducts for oral administration, for increase of bulk density resultsin decrease of volume per dose required.

Illustrative of the mentioned change in bulk density of polymer, anuntreated allyl sucrose crosslinked with acrylic acid polymer wasloosely filled into a volume of 1 cc. The polymer weighed 0.210 gram. Asimilar test of the same polymer after steam treating and millingresulted in a loose bulk density of 0.591 gram per cc.

The polymers treated as described may be readily handled without theundesirable effects experienced with the untreated polymer powder. Thus,when the treated polymers are used, the antacid compositions describedhereinabove may be easily formulated by merely mixing all of theingredients together and subjecting the mixture to the necessarytableting pressure.

An antacid tablet so produced possesses a remarkable superiority overtablets in which the untreated polymers are incorporated. Thissuperiority is manifested in a firmer tablet, having a greatly reducedtendency to crumble, and in a drastically reduced disintegration timewhen placed in an aqueous solution.

Various tests have been conducted to demonstrate the effectiveness ofthe new antacid compositions and their superiority over other forms ofantacid preparations. For example, 1 gram of magnesium carbonate addedto 50 cc. of water with constant stirring has been subjected to theperiodic addition 1 normal hydrochloric acid in 2 cc. increments. It hasbeen found that upon the addition of the first increment of hydrochloricacid the pH has dropped from its initial value of about 8.5 to about5.5. It then climbed rapidly at first and then more slowly for about 10minutes until it leveled off at a pH of about 8.25. At this time afurther increment of the acid was added and substantially the same dropand subse' quent climb in pH occurred. Additional 2 cc. increments of 1normal hydrochloric acid were added at 10-minute intervals with verysimilar results up to the point at which 16 cc. had been added. Upon theaddition of each successive increment the maximum pH gradually becamelower, while the minimum pH fluctuated to a certain extent. Upon theaddition of the next increment of acid, making a total of 18 cc., the pHdropped to about 2.25 and then climbed to a point slightly over 3.0. Onadding a further increment of the acid the pH dropped to about 1.5 andremained at that level.

Similar results were noted upon the addition of 2 cc. increments of 1normal hydrochloric acid to a suspension of 1 gram of magnesiumhydroxide in 50 cc. of water. However, this suspension showed a somewhatgreater variation of pH and the pH climbed more rapidly after eachdecline following the addition of an increment of acid. Moreover, itleveled off more quickly at the higher pH so that increments of acidwere added at -minute intervals. The pH of this suspension dropped toabout 3.5 upon the addition of the first 2 cc. increment of acid andthen climbed to 10.4. Upon the addition of 32 cc. of acid in suchincrements at 5-minute intervals the pH dropped to about 2.25 and thenwas restored to about 7.5. Upon the 'addition of 2 more cc. of acid thepH droppedto 2.0 and was then restored to 4.5, while upon the additionof 2 more cc. of acid, for a total of 36 cc., the pH dropped to about1.75 and remained at that value.

As contrasted with the foregoing tests, a mixture of magnesium hydroxideand a colloidally water-soluble, crosslinked polymer of acrylic acid(Carbopol-934) in equal amounts by weight and totaling 1 gram in 50 cc.of water gave a somewhat similar pattern, but with a maximum pH of 4.5and a minimum of about 2 until 16 cc. of 1 normal hydrochloric acid hadbeen added at 5-minute intervals in 2 cc. increments. Upon the additionof the last increment of the total of 16 cc. of acid the pH dropped from3.0 to 1.75 and remained at that level. The climb in pH from the lowlevel to the high level following the addition of each increment of acidwas more uniform than in the case of magnesium hydroxide alone, and inno case did the maximum pH exceed a value of about 4.5.

To determine the relative speeds of action and ultimate neutralizingeffect of various antacid materials, 1 gram of each was suspended in 50cc. of water, and to this was added at one time a certain number ofcubic centimeters of 1 normal hydrochloric acid, the quantity so addedto each suspension being about two-thirds of the amount previouslydetermined as tending to exhaust the neutralizing action of theparticular antacid material. 32 cc. of acid were added to a suspensionof magnesium oxide, and this was found to climb within 1 minute to a pHof about 9. The same amount of acid added to a suspension of magnesiumhydroxide was found to raise the pH within 2 minutes to about 5 and themmore gradually to about 6.5. This required about minutes. 20 cc. of acidwas added to the magnesium carbonate, and the pH climbed Within 2minutes to about 4.8 and then gradually'climbed to about 5.2 over aperiod of 20 minutes. A suspension of a mixture of .5 gram magnesiumhydroxide and .5 gram of colloidally water-soluble, cross-- linkedpolymer of acrylic acid (Carbopol-934) in50 cc. of water, upon having 16cc. of the 1 normal hydrochloric acid added to it, was found to providea uniform rise in pH from about 1.4 to about 3.5 within 7 minutes, andthen a more gradual rise in pH to about 4 over a total period of 20minutes.

Other experiments conducted with different mixtures of magnesiumhydroxide and a crosslinked polymer of acrylic acid (Carbopol-934), inwhich the proportions of the two incredients varied, showed rathersimilar patterns to be followed upon the addition of 2 cc. increments of1 normal hydrochloric acid'to a suspension of 1 gram of each mixture in50 cc. of water.

Thus, in the case of a mixture of 3 parts by weight of magnesiumhydroxide to 1 part by weight of the 1% polyallyl sucrose crosslinkedpolymer of acrylic acid, 1 gram of the mixture was added to 50 cc. ofwater. An initial pH of about 5.5 was obtained and 2 cc. of 1 normalhydrochloric acid was added. The pH immediately dropped to about 1.75and climbed, in 5 minutes to about 4.7. Additional 2 cc. increments ofacid were added at 5-minute intervals. In each instance the pH droppedto about 1.75 upon addition of the acid and then rose slowly to amaximum value which was, after each successive addition of acid,somewhat lower than the preceding maximum pH. This procedure wasrepeated until a total of 24 cc. of 1 normal acid were added, at whichpoint the pH remained constant at a value of about 2.

Experiments were also conducted with 1 /2 to 1 and 2 to 1 parts byweight of magnesium hydroxide to the Same crosslinked polyacrylic acid.In each case, the addition of the increments of hydrochloric acid weremade promptly after the preparation of the aqueous suspensions and priorto the formation of appreciable quantity of the magnesium salt of thecrosslinked polymer of acrylic acid. Comparisons of the results of theseexperiments and also the results of the experiments utilizing the 1 to 1and 3 to 1 ratios of magnesium hydroxide to the crosslinked polymershowed that the mixtures with the higher magnesium hydroxide contentsestablish a somewhat higher pH after periods of 5 minutes following theaddition of each increment, but, as already noted, the maximum pH wasabout 4.7 for the mixture containing 3 parts of magnesium hydroxide to 1part of the crosslinked polymer. The other mixtures had somewhat lowermaximum pH values. Also, it was found that the mixtures with highermagnesium hydroxide contents served to restore the pH to a higher valuemore quickly.

The effectiveness of the crosslinked acrylic acid polymer in bufferingan antacid solution may be illustrated by repeating the tests set forthabove but using other materials which might be utilized in antacid orother similar pharmaceutical preparations as substitutes for thepolymersconteinplated by the present invention.

For example, an antacid composition was prepared by mixing 3 parts byweight of magnesium hydroxide and 1 part by weight of carboxymethylcellulose. 1 gram of this mixture was added to 50 cc. of water and a pHof about 10.5 was obtained. Upon the addition of 2 cc. of 1 normalhydrochloric acid, the pH dropped to about 3.5 and then rose rapidly toabout 9.5 in about 12 seconds. Additional 2 cc. increments of acid wereadded at 5-minute intervals and in each case the pH dropped to between2.5 and 3.5 and rapidly rose in a matter of seconds to a maximumsomewhatlower than the preceding maximum pH. This procedure wascontinued until a total of 24 cc. of 1 normal acid were added, at whichpoint the pH remained constant at about 3.

Comparison of this test with those in which the polymers contemplated bythis invention were used vividly illustrates the remarkable superiorityof the latter over carboxymethyl cellulose in their ability to buffertheantacid solutions, hence to prevent the undesirable .acid reboundwhich occurs in the human stomach when compositions of the prior art areadministered.

Other materials, such as various ion-exchange resins, pectin acid andalginic acid, have been investigated with a view to their possibleutility as components of antacid compositions in place of the polymersdescribed herein. No suchother material has been found eifective.

While I do not wish to be bound to any theory by which the antacidcompositions according to the present invention produce the superiorresults which maybe obtained, it appears that the results are due inpartto a buffering and sequestering action by the crosslinked polymer ofacrylic acid upon the normally alkaline antacid components which-lowersthe normal pH obtained with these substances and retards the formationof alkaline salts of the crosslinked polymer of acrylic acid.Consequently, no excessive alkalinity is produced which results inunwanted acid rebound. Hence under conditions of hyperacidity in thestomach, the customary tendency of these alkaline antacid components todrastically increase the pH of the stomach while the excess hydrochloricacid in the stomach is being neutralized is eliminated. When theiantacid compositions of the present invention are placed in plainwater, without hydrochloric acid, the pH of the resulting aqueoussuspension will increase upon standing for a short period of time (ofabout 5 to 10 minutes) until the pH is in the alkaline range. This isbelieved to indicate salt formation between the antacid component andthe polymer of acrylic acid. The alkaline salts of the crosslinkedpolymer of acrylic acid does not have the property of buffering thestomach in the range below a pH of 5.5, and preferably below 4.5, whichis ill one of the desirable properties of the compositions of thepresent invention.

While a number of embodiments of the invention have been described inconsiderable detail and various modifications have been suggested, itwill be understood that various other modifications and embodiments maybe made within the scope of the appended claims.

What is claimed is:

1. A pharmaceutical antacid preparation comprising a colloidallywater-soluble polymer of acrylic acid crosslinked with polyallylsucrose, and a nontoxic antacid selected from the group consisting ofthe oxide, hydroxide, carbonate and hydroxy salts of magnesium.

2. The pharmaceutical antacid preparation according to claim 1 whereinthe antacid is magnesium hydroxide.

3. The pharmaceutical antacid preparation according to claim l whereinthe antacid is magnesium oxide.

4. The pharmaceutical antacid preparation according to claim 1 whereinthe antacid is magnesium carbonate.

5. A pharmaceutical antacid preparation comprising a non-toxiccolloidally water-soluble polymer of acrylic acid crosslinked with apolyhydroxy compound wherein the hydrogen atoms of at least 3 hydroxylgroups are replaced with unsaturated aliphatic radicals, and a nontoxicantacid selected from the group consisting of the oxide, hydroxide,carbonate and hydroxy salts of magnesium.

6. A pharmaceutical antacid preparation comprising a nontoxiccolloidally water-soluble polymer of acrylic acid crosslinked with apolyhydroxy compound wherein the hydrogen atoms of at least 3 hydroxylgroups are replaced with unsaturated aliphatic radicals having from 2 to4 carbon atoms, and a nontoxic antacid selected from the groupconsisting-of the oxide, hydroxide, carbonate and hydroxy salts ofmagnesium.

7. A pharmaceutical antacid preparation comprising a nontoxiccolloidally water-soluble polymer of acrylic acid crosslinked with asubstituted polyhydroxy compound having at least 3 double bondsavailable for crosslinking purposes, and a non-toxic antacid selectedfrom the group consisting of the oxide, hydroxide, carbonate and hydroxysalts of magnesium, said polymer having been subjected to the action ofsteam to form a porous cake, said cake then having been dried and milledto a predetermined particle size.

8. A pharmaceutical antacid preparation comprising a non-toxiccolloidally water-soluble polymer of acrylic acid crosslinked with anunsaturated ether having at least 3 double bonds available forcross-linking purposes, and a non-toxic antacid selected from the groupconsisting of the oxide, hydroxide, carbonate and hydroxy salts ofmagnesium.

9. A pharmaceutical antacid preparation comprising a non-toxiccolloidally water-soluble polymer of acrylic acid crosslinked with anunsaturated saccharide ether having at least 3 double bonds availablefor crosslinking purposes and a non-toxic antacid selected from thegroup consisting of the oxide, hydroxide, carbonate and hydroxy salts ofmagnesium.

10. A pharmaceutical antacid preparation comprising a colloidallyWater-soluble polymer of acrylic acid crosslinked with from about 0.75%to about 1.5% of polyallyl sucrose, and a non-toxic antacid selectedfrom the group consisting of the oxide, hydroxide, carbonate and hydroxysalts of magnesium.

11. A pharmaceutical antacid preparation comprising 12 a colloidallywater-soluble polymer of acrylic acid crosslinked with from about 0.75%to 1.5 of polyallyl sucrose and magnesium hydroxide, the crosslinkedpolymer and the magnesium hydroxide being present in a ratio of 1 partby weight of the former to about 1 to 6 parts by Weight of the latter.

12. A pharmaceutical antacid preparation comprising a non-toxiccolloidally water-soluble polymer of acrylic acid crosslinked with apolyhydroxy compound wherein the hydrogen atoms of at least 3 hydroxylgroups are replaced with allyl groups and a non-toxic antacid selectedfrom the group consisting of the oxide, hydroxide, carbonate and hydroxysalts of magnesium.

13. A pharmaceutical antacid preparation comprising a non-toxiccolloidally Water-soluble polymer of acrylic acid crosslinked with apolyhydroxy alcohol wherein the hydrogen atoms of at least 3 hydroxylgroups are re placed with unsaturated aliphatic radicals, and a nontoxicantacid selected from the group consisting of the oxide, hydroxide,carbonate and hydroxy salts of magnesium.

14. A pharmaceutical antacid preparation comprising a colloidallywater-soluble polymer of acrylic acid crosslinked With from about 0.75%to about 1.5 of polyallyl pentaerythritol, and a non-toxic antacidselected from the group consisting of the oxide, hydroxide, carbonateand hydroxy salts of magnesium.

15. A pharmaceutical antacid preparation comprising a non-toxiccolloidally water-soluble polymer of acrylic acid crosslinked with anunsaturated ester having at least 3 double bonds available forcrosslinking purposes, and a non-toxic antacid selected from the groupconsisting of the oxide, hydroxide, carbonate and hydroxy salts ofmagnesium.

16. A method of treating hyperacidity which comprises administering asuitable quantity of a composition comprising a non-toxic colloidallywater-soluble polymer of acrylic acid crosslinked with a polyhydroxycompound wherein the hydrogen atoms of at least 3 hydroxyl groups arereplaced with unsaturated aliphatic radicals having from 2 to 4 carbonatoms, and a pharmaceutically suitable substance of the group consistingof the oxide, bydroxide, carbonate and hydroxy salts of magnesium.

17. A method of treating hyperacidity which comprises administering asuitable quantity of a composition comprising a colloidallywater-soluble polymer of acrylic acid crosslinked with from about 0.75%to about 1.5 of polyallyl sucrose, and an amount of a non-toxic an tacidsubstance selected from the group consisting of the oxide, hydroxide,carbonate and hydroxy salts of magnesium, said non-toxic antacidsubstance ranging from an equal amount by weight up to 6 times theweight of said polymer of acrylic acid.

References Cited in the file of this patent UNITED STATES PATENTS2,477,080 Necheles July 26, 1949 2,541,142 Zief Feb. 13, 1951 2,798,053Brown July 2, 1957 OTHER REFERENCES Swaftord: I. A. Ph. A. (pract. ed.),vol. 16, No. 3, May 1955, pp. 171-172.

Fuchs: Drug and Cosmetic Ind., vol. 64, No. 6, June 1949, pp. 692 and693.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No,2,912,358 November 10, 1959 Ludwig A.,- Staib, Jr

It is hereby certified that error appears in the printed specificationof the above numbered patent requiring correction and that the saidLetters Patent should readas corrected below.

Column 1, line 36, for "bring" read brings column 4, line 5, after"substantially" insert ---a1 1==-; column 5, line 29, for "able" readalba column 9, line 54, for "incredients" read ingredients Signed andsealed this 26th day of April 196C!u (SEAL) Attest:

KARL, H. AXLINE ROBERT C. WATSON Attesting Oflicer Commissioner ofPatents

1. A PHARMACEUTICAL ANTACID PREPARATION COMPRISING A COLLOIDALLYWATER-SOLUBLE POLYMER OF ACRYLIC ACID CROSSLINKED WITH POLYALLYLSUCROSE, AND A NON-TOXIC ANTACID SELECTED FROM THE GROUP CONSISTING OFTHE OXIDE, HYDROXIDE, CARBONATE AND HYDROXY SALTS OF MAGNESIUM.